Metabolomic approach to predict new anti-inflammatory extracts with in vivo outstanding mechanism of action

Novel inhibitors able to inhibit both cyclooxygenase (COX) and lipoxygenase (LOX) pathways are currently desirable, since they could display high efficacy and low side effects. Some extracts from Asteraceae family showed in vitro dual inhibition of COX-1 and 5-LOX, and biomarkers correlated with this feature were determined [1]. Thus, some of the active extracts (EtOH-H2O 7:3, v/v) were evaluated through in vivo anti-inflammatory assays (Ethical animal committee approved, #16/2016), which can evaluate exactly both main inflammatory pathways: COX and LOX (inhibition of ear oedema and neutrophil recruitment, respectively; n = 8, 0.5 mg/ear). Prestelia eriopus, Viguiera robusta, Viguiera trichophylla and Tithonia diversifolia proved to display in vivo outstanding mechanism of action by inhibition of both COX and LOX pathways, similarly positive controls (P > 0.05 compared to indomethacin and dexamethasone, respectively), and different of negative control (vehicle, P < 0.05). These active extracts and other six inactive extracts were analysed by high performance liquid chromatography coupled to high resolution mass spectrometry (HPLC-HRMS) analysis, and subjected to in silico studies using O2PLS-DA. The biomarkers of in vivo dual activity were determined, and new model of prediction of active extracts were created and validated (R² and Q² > 0.5). Twenty new extracts from a different family (Lauraceae) were also evaluated in the same run at HPLC-HRMS, together with extracts used to train the prediction model. The model was efficient to predict new biologically active extracts, which have determined biomarkers, even if they are from different families. One of predicted active extracts proved to be able to do in vivo inhibition of COX and LOX pathways. Thus, this new model can be useful to predict new anti-inflammatory extracts, which have innovative mechanism of action, using only HPLC-HRMS data.

CAPES, CNPq, FINEP, FAPEMIG and Asterbiochem.

[1] Chagas-Paula DA. et al. Planta Medica 2015; 81: 450 – 458.